Most recently, I was one of the first people to congratulate
Mark Harrington upon the announcement of his MacArthur "genius award"
last year. The first AIDS activist to win the award and probably the first
openly gay male to boot. The rumor was that friends had been nominating
him for years since he left ACT UP in 1993 in what by all accounts was a
bitter and public split with the rank and file AIDS community. The irony
of the award and the point of the rumor was that the MacArthur people were
unwilling til quite recently to give a quarter of a million dollars to someone
who might not live to spend it all. My how times have changed. Now that
Mark has become the subject of a much deserved media spurt, we can perhaps
put all of this into perspective.

Let's begin at the beginning.

Compassionate use; Expanded access; Parallel track; Accelerated
Approval ­ terms all used interchangeably and which resonate deeply
with the earliest days of grassroots activism ­ were all attempts to
put drugs into the bodies of desperately ill people while the drug companies
jumped through the prescribed regulatory hoops. But, Harrington, the brains
behind ACT UP's well-orchestrated campaign to change FDA regulations was
not deterred by labels. He and a small cadre of like minded laymen that
included Jim Eigo, John Bohne, Tom Cunningham, Ken Fornataro and Iris Long
had devised most of the labels anyway.

As he stood behind the podium during the July 21, 1992
Plenary Session of the Eighth International Conference On AIDS in Amsterdam,
Mark was already acknowledged on both sides of the stage as ACT UP's ambassador
to the scientific community. A bright, pugnacious graduate of Harvard's
rough and tumble queer underground, he perfected a manner of dealing with
drug companies that he would later call "the two-pronged approach":
charm and erudition when they seemed willing to play ball; vituperation
and calculated mayhem when they didn't.

Admirers were often struck by the subtle changes in his
hair color through the course of the year: from brown to reddish blonde
and back again. After Amsterdam that would not be the only thing they noticed
changing.

"What is the point of streamlining access and infrastructure",
he would ask the assembled dignitaries, "when the result is merely
to replace AZT with additional mediocre, toxic, expensive nucleoside analogues?"

Monotherapy was the Holy Grail of accepted AIDS treatment.
The only problem was that the reigning gold standard of the group; the one
that dozens upon dozens of experiments all used as a benchmark every year--AZT--didn't
work; at least, not in most people, beyond the first six months. Ddc and
ddi were in the pipeline, but as a Barron's magazine article would point
out, the lion's share profit from any new class of drugs traditionally accrued
to the drug approved first in time. It would be another year before researchers
such as Aaron Diamond's Martin Markowitz and others would stumble upon the
idea of combining drugs in a cynergistic cocktail of three or more unrelated
drugs, not unlike chemotherapy among cancer patients. And , yes, for all
intents and purposes, protease inhibitors looked like just one more "mediocre
drug."

By the time information began to leak out about a little
known experiment tucked away in one of the satellite labs belonging to drug
giant, Hoffmann LaRoche, hope was beginning to fade that any form of chemotherapy
would stop the spread of HIV within the body. The virus' genetic material
was simply too unstable and thus quick to evade whatever regimen combined
with the body's defenses to eliminate it. By the spring of 1994, when the
FDA sponsored clinical trials, tests would confirm that at 1800 mgs a day,
Roche's "anti-protease" drug was no better than AZT.

But, to someone at the end of their tether--resistant to
AZT, blood work headed south--one more shot at even a mediocre drug sounded
awfully good. Hope was the only medicine keeping some people alive. Stung
by criticism that, after his speech in Amsterdam, he was only interested
in advancing the very narrowest interests of people in the earliest stages
of disease (an accusation he vigorously denies), Mark proceeded to form
a parallel group called the Treatment Activist Group, or TAG.

With seed money from AmFar he was able to travel extensively,
put out a first-rate newsletter, and for the first time not worry about
coming hat in hand to an increasingly restive membership. Based on Harvard's
famous men's clubs, the public at large was welcome "to observe"
TAG's meetings, but voting was restricted to those who had been tapped for
the honor.

At first, ACT UP and TAG worked together. For policy wonks
it was a bonanza. They could now discuss the intricacies of Parrallel Track
and Accelerated Approval twice as often each week. TAG even picked up the
check at a post-demo breakfast following a blockade of the corporate headquarters
of Hoffmann-LaRoche during which approximately 100 members of both groups
handcuffed themselves to strategic entry gates. One of the demands was that
they release the results of their Saquinavir studies.

Then, one summer evening in 1994 as the skeleton crew of
ACT UP's Treatment and Data Committee, a virtual Harrington alma mater,
gathered to discuss the buzz coming out of Yokahama (site if the 10th International
Conference) someone produced a letter with a faintly familiar letterhead.
But there, instead of ACT UP's trademark white letters on a black square
was the word "TAG".

Substantively, the letter, addressed to FDA head, David
Kessler, was a proposal to submit Roche's protease inhibitor, now called
Saquinavir, to the rigors of a Large Simple
Trial. It was
signed by Harrington and three other former members of ACT UP. The proposal
elicited initial excitement. LSTs were one of those ideas that seemed to
make the rounds from time to time among the autodidactic world of treatment
activists. Its main utility seemed to be its ability to incorporate disparate
data along stratified lines of inquiry, thus, for example, enabling a biostatistician
to credibly state whether Saquinavir was overall better than AZT or ddc
or--bat's wings--if enough people enrolled.

The problem was that at 16,000 people, Harrington's proposal
would have taken years to complete and with nearly a dozen other companies
planning protease inhibitors of their own, there was no telling how it might
effect future trials or even whether current enrollees would continue once
other drugs became available. Gradually, as the proposal made the rounds
from New York to Southern California, the self-styled "treatment community"
was thrown into chaos.

In the face of blistering criticism from an array of mainstream
advocacy groups and researchers, TAG reacted initially by digging in its
heels. Only "large-scale, community based clinical trials of new AIDS
drugs" would provide the answers they sought.

And the questions were growing. Morale within ACT UP was
at perhaps its lowest point since the results of the Concorde trials, a
European sponsored set of protocals which first revealed AZT's inadequacies.
Roche's competitors were warning that protease inhibitors exhibited evidence
of cross-resistance--meaning that resistance to one might confer resistance
to some or all of the others after a few months. Roche itself added to the
confusion by confirming that a new, improved formulation was in the works
even as they were vigorously pursuing approval of the old one.

But, by far the most serious question was whether approval
of Saquinavir would be delayed due to the TAG proposal. That it would be
readily available to anyone who enrolled did little to dampen the outrage.
Harrington has never acknowledged that if some of the sentiments expressed
in the 1994 letter, co-signed by him and David Barr and other members of
TAG, had been implemented--even without creating a choke point in the approval
process--the possibility existed that people would still be dying who might
not have had to. For example, there was the issue of dosage. It would be
another year before Roche was even sure of what the optimal dose would be.
A large simple trial in 1994 would have committed 16,000 people to a protocol
that was less than half the dose it should have been.

By summer's end, comrades in arms were no longer listening
to each other. The heat generated by the controversey was so great it would
eventually reach Kessler himself. By October of 1994, he was forced to convene
a panel to review the process by which companies gained Accelerated Approval
of their products and after a day of bitter denunciations and counter-charges
the system was reaffirmed with minor changes.

Following the FDA shootout, TAG decided to initiate what
would subsequently become their *modus operandi*--dealing directly with
company headquarters. Roche, which is actually a multi-national of Swiss
origin, was also seeking a way to dampen months of toxic p.r. By November,
both sides were engaged in secret negotiations. Roche even took the unprecedented
step of sending its CEO all the way from Basel to join the talks.

By early 1995, exactly two years after TAG and ACT UP stormed
its U.S. headquarters, Roche had worked out a temporary truce. In return
for TAG's not actively opposing its New Drug Application, Roche agreed to
a Parallel Track program for their drug. Saquinavir would be made available
to over 4,000 people with AIDS. Other groups, including ACT UP/New York
formed a working group and a lottery system was worked out. Entry criteria
included a limit of 50 t-cells and soon that became the industry standard
as other companies were pressured into setting up similar programs.

All went smoothly at first. Private physicians would serve
as enrollment sites instead of the traditional institutional center. Forms
were made as simple as possible to limit paperwork and there were remakably
few complaints according to advocates who monitored the lottery. But built
into the program was one compromise of gigantic proportions. The dosage
that would be prescribed was less than half what was beginning to be known
about Saquinavir's effectiveness. Scientists at a research lab at Stanford
were now saying that to adequately ensure cross-resistance was kept at a
minimum, Saquinavir should be taken at 3,600 mgs. a day, and more likely
at 7,200 mgs. a day rather than the 1,800 originally proposed to the FDA.

Doing a super high dose study of Saquinavir during the
lottery process was never an option. The problem was that at some point
it had become an article of faith that Roche could not possibly manufacture
more drug. To do an optimal dose study using the lottery volunteers would
have meant halving or even quartering the available slots.

Although the lottery for the first 2,200 slots was held
in July, actual drug did not begin arriving until late October. Another
2,200 were randomly chosen in October bringing the total to 4,400 PWAs with
free access to Saquinavir. Then, just as suddenly as drug began arriving,
the supply was cut off. Why? The FDA had announced Saquinavir's approval.
Lottery winners were told in no uncertain terms that the study had ended
along with their supply of drug. As a prerequisite for approval, Roche had
to have known as early as the previous spring that enough drug to fill drug
store shelves by the first of the year would be available. Yet, no one demanded
that they continue the program or that another dosage arm be added.

As Larry Kramer, put it to the New York Times: "Hoffmann
acquired significant pre-marketing sales information from the clinical data
it demanded for entry into the lottery...insuring a market success for the
drug even before its true effectiveness in the treatment of AIDS has been
defined by clinicians."

The same danger existed for winners of the other activist-approved
lotteries, including Merck and Abbott. Both experienced delays in supply
and, wondrously, both anticipated FDA approval within months. The question
again arises, where is all this drug going to come from? Was it being stockpiled?
Were drug companies lying to activists when the original lotteries were
designed? A lot of people eschewed other alternatives while waiting for
these drugs.

Much of the blame was placed with the extremely lengthy
lead time Roche and the other drug companies required to plan output. The
plant specifications for Saquinavir production were set in stone over a
year before the first case left the loading dock. To have changed the specs
in mid-stream would have meant reassembling a team of chemical engineers,
consultants, and various bean counters most of whom were engaged in other
projects by the time the dosage and demand miscalculations were discovered.

One reason given for the lack of outrage in the community,
was that along with Saquinavir, two other nukes were also approved by the
FDA thus helping to tamp down the fires. People simply left the delayed
programs in order to make use of some other regimen. But, one wonders whether
at least as much culpability lies with the fact that their leaders, including
Mark Harrington, were themselves handcuffed to the very programs they helped
design.